The metal-catalyzed C À Hb orylation reaction has garnered profound interest in recent decades based on the synthetic utility of the resulting CÀBbond and the ability to selectively install ab oron substituent without ap re-existing functional group. [1][2][3] Early work in the area of metal-catalyzed CÀH borylation reactions utilized catalysts that were stericallycontrolled, avoiding ortho C À Hbonds in arenes and favoring primary C À Hb onds for alkanes. [4] Starting in 2008, new systems were developed that utilized directing groups to achieve alternative selectivity patterns (ortho-o rmetadirected). Thea pproaches used to achieve directed CÀH borylation are diverse,b ut, the key to achieving the desired directing effect has been to modify the catalyst in away that the directing interaction does not form ac oordinatively saturated 18-electron complex, which then has no open site for activation of the CÀHb ond. Using these approaches, many directing groups have been used to access functionalized arylboronates.

Taking advantage of the insights gained in substratedirected C À Hb orylation reactions,o ur group extended the available directing groups to phosphines.Our initial efforts in phosphine-directed CÀHb orylation were reported in 2014, providing the first example of ag eneral phosphine-directed CÀHfunctionalization [35][36][37][38][39][40][41][42][43][44] and providing access to phosphine boronate esters from valuable phosphine precursors. [23] The key to obtain the desired reactivity in these studies was running the reaction without added ligand. We proposed am echanism in which the phosphine substrate served as the ligand during the catalytic reaction (Scheme 1). While these catalytic conditions were useful in the synthesis of aseries of phosphine boronates,t he role of the substrate as ligand severely limited the phosphines that were compatible with the reaction conditions.T he proposed active catalyst utilizes the substrate as aC ,P-bound ligand in which the X-type ligand interaction of the arene carbon with iridium served to replace one of the boryl ligands of the known iridium(III)trisboryl active catalyst [45] (Scheme 1), maintaining an open coordination site for CÀHactivation upon phosphine coordination. We herein report ag eneral method to rapidly form as eries of ambiphilic phosphine boronates by phosphine-directed CÀH borylation, utilizing au nique cationic iridium complex and aknown silylquinoline that provide complimentary reactivity in this selective C À Hborylation reaction.

Am ore general catalyst system for phosphine-directed CÀHb orylation was initially sought by examining the synthesis of pre-formed P, C-bidentate ligands that could mimic the proposed active catalyst (Scheme 1). These efforts did not provide aviable catalyst and were not consistent with our goal to identify readily available pre-catalysts and ligands for this transformation. As eries of known substrate-directed C À H borylation conditions,which were expected to be compatible with phosphines,w ere examined with 3-methoxybenzyldicyclohexylphosphine (Table 1), as ubstrate that was unreactive under the original reaction conditions (entry 1). [23] By identifying optimal reaction conditions for this problematic substrate,amore general set of reaction conditions across awide range of phosphines was expected.

Thefirst set of conditions examined were those developed by our group for amine-directed CÀHb orylation, which utilize ah emi-labile ligand (N-benzylaminopyridine, 2, Scheme 1. Proposed active catalyst for phosphine-directed CÀHborylation with no added ligand.

Figure 1), [18,27] providing no evidence of the formation of 1 (Table 1, entry 2). Miyaura reported ester-directed CÀH borylation using an electron-deficient phosphine ligand (tris-[3,5-bis(trifluoromethyl)phenyl]phosphine, 3); [10] no C À H borylation was observed under Miyaurasoriginal conditions nor with alternative solvents and elevated temperature (entry 3). Smith and Maleczka reported silane-based bidentate ligands (4)t hat proved compatible with ar ange of directing groups, [25] but were also unreactive with the test phosphine (entry 4). Ac ationic iridium complex with ar igid bidentate ligand was examined with the idea that the cationic nature of the complex could open an additional coordination site for directed CÀHb orylation (see above). Commercially available complex 5 was found to provide modest, but promising,conversion to boronate 1 (entry 5).

Ther eactivity of cationic pre-catalyst 5 was surprising considering the general consensus that the active iridium complex should be electron-rich. [46,47] This cationic complex, however, was the only reactive catalyst for the studied phosphine.The reactivity of the cationic complex is proposed to result from obtaining the required two open coordination sites by replacing one of the -Bpin ligands of the known iridium(III)trisboryl complex with anon-coordinating ligand. Ther esulting iridium(III)bisboryl complex (Figure 2, A)h as the ability to access two open coordination sites for the Lewis basic phosphine and the adjacent CÀHb ond. Based on this realization, am ore effective bidentate ligand was sought to increase the generality of the reaction. 3,4,7,8-Tetramethyl-1,10-phenanthroline (TMPHEN), ac ommonly used ligand for non-directed C À Hborylation reactions, [48][49][50] was expected to form amore active cationic complex (B)while maintaining an open coordination site for directed CÀHb orylation.

Initial examination of TMPHEN with commerciallyavailable cationic pre-catalysts [Ir(COD) 2 ]BF 4 resulted in no reactivity (Table 2). Switching the boron source from bis(pinacolato)diboron (B 2 pin 2 )t op inacolborane (HBpin), however, drastically increased the reactivity.W ith 1.7 equivalents of pinacolborane,a72 %conversion was observed after 24 hat130 8 8C. Increasing the equivalents of pinacolborane to 6.7 provided full conversion, but the ratio of monoborylation product (1,T able 2) to bisborylation product (1' ')was modest (87:13). Reducing the equivalents of pinacolborane to 3.3 improved the selectivity for 1 to 96 %w hile maintaining ah igh conversion. Lowering the temperature to 110 8 8C further improved the selectivity without as ubsequent loss of conversion, providing 99 %c onversion and a9 9:1r atio of 1:1' '.B 2 pin 2 is the most commonly-used boron source in CÀH borylation reactions.Formation of the active catalyst from the pre-catalyst is typically accelerated with HBpin, but the increased concentration of hydrogen gas as the reaction progresses can retard the reaction. [47] In this study,f ull conversions are observed with HBpin, suggesting that hydrogen gas does not hinder the reaction significantly.F urther mechanistic studies are required to fully understand this effect.

Theo ptimized reaction conditions were utilized for as eries of benzylic phosphines to examine steric and electronic influences on the reaction efficiency. To simplify isolation and purification of these electron rich phosphines, the crude reaction mixture was treated with BH 3 •THF to form the borane complex. [23,51] High yield and selectivity for the ortho monoborylation product was observed in most cases (Table 3). Diphenyl-and dicyclohexyl-substituted benzylphosphines worked well under the reaction conditions to provide the corresponding boronate esters (6 and 7,entries 1 and 2). 3-and 4-substituted benzylic phosphines provided good yields of 8-11 (entries 3-5), demonstrating compatibility with chlorine or methoxy substituents.T he ortho-substituted benzylic phosphines,h owever,w ere prone to additional reactions that resulted in low yields.T he 2-chloro-substituted arene,for example,provided both CÀHand CÀCl borylation (71:29). [52] Encouraged by the generality of the CÀHborylation with benzylic phosphines,commonly used phosphine ligands were examined under the reaction conditions.I ndole-based phosphines were readily borylated, providing 12-14 in high yield and selectivity for monoborylation products (Figure 3).

Biphenyl-based phosphines,h owever,w ere less reactive under the reaction conditions using the cationic iridium system. Treatment of these phosphines with the silylquinoline ligand conditions reported by Smith [25] (4,T able 1, entry 4) provided high conversions to the desired borylation products when B 2 pin 2 was used as the boron source.T herefore, borylation of the commonly used ligands CyJohnPhos, DavePhos,a nd MePhos, [53] provided the corresponding boronate esters (15-17)i ng ood yields upon protection. In the case of 15,selectivity was reduced to 83:17 mono:bis (15:15' ').

To verify that the C À Hb orylation of DavePhos (to form 16) was directed by the phosphine,a nd not the amine,t he structure of 16 was confirmed by X-ray crystallography (see Figure 4). Borylation of diphenylphosphinoferrocene (FcPPh 2 )w as also examined;u nder both sets of conditions, competitive bisborylation was observed. Isolation of 18, however, was achieved in 43 %yield from a50:25:25 mixture of 18:18' ':FcPPh 2 .

Thei ncreased reactivity of certain substrates (especially CyJohnPhos and diphenylphosphinoferrocene) toward bisborylation led to the examination of conditions that could selectively provide polyborylated products.T reatment of CyJohnPhos with excess B 2 pin 2 (2 equiv) at 130 8 8Cp rovided bisborylated product 15' ' (> 90 %selective for 15' ' over 15)i n 61 %y ield (Scheme 2). Subjecting diphenylphosphinoferrocene to the standard cationic iridium conditions (3.3 equiv HBpin at 130 8 8C) provided bisborylation (18' ')a st he sole Scheme 2. Phosphine-directed polyborylation reactions. [a] 1.25 mol % [Ir(COD)OMe] 2 ,7.5 mol % 4,2equiv.B 2 pin 2 ,t oluene,1 30 8 8C, 48 h (> 90:10 15' ':15); then BH 3 •THF. [b] 2.5 mol %[(COD) 2 Ir]BF 4 ,2 .5 mol %TMPHEN, toluene, 3.3 equiv.HBpin, 130 8 8C, 24 h( > 99:1 18' ':18); then BH 3 •THF. [c] 2.5 mol %[(COD) 2 Ir]BF 4 ,2 .5 mol % TMPHEN, toluene, 10 equiv.HBpin, 110 8 8C, 24 h(67:33 6' ':6); then BH 3 •THF. [d] 2.5 mol %[(COD) 2 Ir]BF 4 ,2 .5 mol %TMPHEN, dioxane, 1.7 equiv.H Bpin, 100 8 8C, 24 h(93 %conv.; 63:37:0 19:20:21); then BH 3 •THF. [e] 2.5 mol% [(COD) 2 Ir]BF 4 ,2 .5 mol %TMPHEN, toluene, 3.3 equiv.H Bpin, 100 8 8C, 24 h(99 %conv.; 14:77:8 19:20:21); then BH 3 •THF. [f ]2.5 mol %[(COD) 2 Ir]BF 4 ,2 .5 mol %TMPHEN, toluene, 10 equiv.H Bpin, 130 8 8C, 72 h(100 %conv.; > 99 % 21); then BH 3 •THF.

product. Likewise,benzyldiphenylphosphine could be pushed to bisborylation product 6' ' (67 %selective for 6' '). Encouraged by these results,t ribenzylphosphine was examined under av ariety of borylation conditions,u ltimately providing moderate to good yields of mono-( 19), bis-( 20), and trisborylated (21)p roducts upon purification by column chrohe synthesis of polyborylated products is expected to provide intriguing polyfunctionalized phosphines and useful comparisons with monoborylated products as organocatalysts [54][55][56][57][58][59][60][61] and ambiphilic catalysts and ligands [62,63] upon removal of the borane protecting group.

Removal of the borane protecting group was examined to demonstrate the facile access to av ariety of ambiphilic phosphine boronates with steric, electronic,a nd geometrical variations.M onoborylated phosphines 22-24 and polyborylated phosphines 25 and 26 were readily accessed upon heating in diethylamine with yields ranging from 60-95 % (Scheme 3).

Upon deprotection of the phosphine,a ni nteraction between the Lewis basic phosphorus atom and the Lewis acidic boron atom (of -Bpin) becomes possible. [16] To examine if such an interaction is taking place,t he 11 BNMR spectra were compared to the corresponding protected phosphines.If an interaction was taking place,a nu pfield chemical shift would be expected. As shown in Table 4, no significant chemical shift changes were observed, consistent with no interaction in the solution state.T he lack of interaction was probed in the solid state by X-ray crystallography of 23 (Figure 5). As expected from the spectral data, no interaction was observed for 23 in the solid state.

In summary,efficient methods for phosphine-directed C À Hborylation have been reported. These catalysts were active in aw ide range of benzylic and aryl phosphines including indole-and ferrocene-based substrates.P olyborylation of aseries of phosphines was also possible.Deprotection of the phosphine boronates with diethylamine provided as eries of ambiphilic phosphine boronates,n one of which showed interactions between the free phosphorus and the boron atoms.

15 30.5 22 30.9 16 31.1 23 31.6 18 32.8 24 33.2 18' ' 32.6 25 33.5 20 31.7 26 31.7